chr2-70921196-C-T

Variant names:

• chr2-70921196-C-T
• rs145436494
• NM_012476.3:c.346C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_012476.3(VAX2):​c.346C>T​(p.Arg116Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000812 in 1,613,696 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R116H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000098 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000079 (1 hom.)
• Consequence: VAX2 NM_012476.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.15
• Publications: 2 publications found

Genes affected

VAX2 (HGNC:12661): (ventral anterior homeobox 2) This gene encodes a homeobox protein and is almost exclusively expressed in the ventral portion of the retina during development. In mouse studies, this gene was found to be required for the correct formation of the optic fissure and other aspects of retinal development. [provided by RefSeq, Sep 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VAX2	NM_012476.3	c.346C>T	p.Arg116Cys	missense_variant	Exon 2 of 3	ENST00000234392.3	NP_036608.1
VAX2	XM_011532750.4	c.346C>T	p.Arg116Cys	missense_variant	Exon 2 of 4		XP_011531052.1
VAX2	XM_011532751.4	c.346C>T	p.Arg116Cys	missense_variant	Exon 2 of 4		XP_011531053.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VAX2	ENST00000234392.3	c.346C>T	p.Arg116Cys	missense_variant	Exon 2 of 3	1	NM_012476.3	ENSP00000234392.2
VAX2	ENST00000432367.6	n.169C>T		non_coding_transcript_exon_variant	Exon 2 of 15	5		ENSP00000405114.2
VAX2	ENST00000646783.1	n.-12C>T		upstream_gene_variant				ENSP00000495231.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152176 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000108 AC: 27 AN: 250516 AF XY: 0.000140

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000794 AC: 116 AN: 1461402 Hom.: 1 Cov.: 30 AF XY: 0.0000908 AC XY: 66 AN XY: 727002

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000302 AC: 26 AN: 86178

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53190

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000675 AC: 75 AN: 1111904

Other (OTH) AF: 0.0000994 AC: 6 AN: 60388

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152294 Hom.: 1 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74456

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000121

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.346C>T (p.R116C) alteration is located in exon 2 (coding exon 2) of the VAX2 gene. This alteration results from a C to T substitution at nucleotide position 346, causing the arginine (R) at amino acid position 116 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.88	P
Vest4		0.74
MVP		1.0
MPC		0.31
ClinPred		0.26	T
GERP RS		5.4
Varity_R		0.50
gMVP		0.49
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145436494; hg19: chr2-71148326; COSMIC: COSV52267071; COSMIC: COSV52267071;